The alpha 7-nicotlnic acetylcholine receptor is an investigational target for the development of new drugs to improve brain function in schizophrenia. The target is supported by (1) electrophysiological evidence for its participation in the sensory gating disturbances that are an endophenotype found in persons with schizophrenia, (2) genetic evidence for abnormalities involving CHRNA7, the gene for the a7-nicotinic receptor subunit, and (3) pharmacological evidence for possible therapeutic effects of nicotine as well as more specific a7-nicotinic agonists. The hypothesis that emerges is that persons with schizophrenia have diminished expression of the a7-nicofinic receptor on inhibitory interneurons in the hippocampus and thalamus. Increased activation of these inhibitory interneurons, by enhanced pharmacological stimulation of this diminished population of a7-nicofinic receptors, would improve patients'neurocognitive abilities, particularly their characteristic problems in sustained attention. UCI-40083, an allosteric modulator at the a7- nicotinic receptor, has unique properties as a candidate therapeutic at this site. UCI-40083 has the ability to selectively increase ion currents through the a7-nicotinic receptor channel while retaining fidelity to the agonist-induced kinetics of channel opening and closing, making it a safe and potentially effective drug to increase cholinergic neurotransmission at this receptor. It has shown promising safety and efficacy in animal models. This National Cooperative Drug Discovery Development Group will take the next step to evaluate UCI-40083 as a potential therapeutic for schizophrenia by performing a first-in-humans Phase 1 pharmacokinetics and safety trial, a Phase 1b preliminary dose-finding trial in schizophrenia, and an initial Phase 2 proof-of-principle clinical trial in schizophrenia to determine effects on neurocognition, with additional assessments involving brain imaging, pharmacogenomics, psychosocial function, and positive and negative symptoms. The drug will be synthesized through the University of California Irvine, where it was discovered, and tested at the University of Colorado Denver, which has previous experience with the clinical evaluation of agonists of the a7-nicotinic receptor for neurocognitive dysfunction in schizophrenia. Public Health Relevance: Persistent neurocognitive deficits, psychosocial disability, and negative symptoms are evidence that current neuroleptic therapies, which primarily inhibit dopamine D2 receptors, are insufficient treatment for schizophrenia. Alpha7-nicofinic receptor activation is a potential additional target for drug therapy. UCI- 40083 is the first of a new class of drug that can improve a7-nicotinic receptor function.